Aminobiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions

ABSTRACT

Aminobiguanides and the use of same as antimicrobial agents in pharmaceutical compositions are disclosed. The aminobiguanides are useful in the preservation of pharmaceutical compositions, particularly ophthalmic pharmaceutical compositions and compositions for treating contact lenses. The compounds are especially useful for disinfecting contact lenses.

CLAIM FOR PRIORITY

[0001] The present application is a divisional of U.S. patentapplication Ser. No. 09/581,952 (allowed) filed Aug. 3, 2000, whichclaims priority from International Patent Application Serial No.PCT/US98/27332, filed Dec. 18, 1998; which claims priority from U.S.Provisional Application Serial No. 60/068,330 filed Dec. 19, 1997.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to aminobiguanides havingantimicrobial activity, and to the use of these aminobiguanides inpharmaceutical compositions. More specifically, the invention isdirected to use of the subject aminobiguanides in compositions andmethods for disinfecting contact lenses, and to the use of thesecompounds to preserve various types of pharmaceutical compositions frommicrobial contamination, particularly ophthalmic and otic pharmaceuticalcompositions.

[0003] Contact lenses are exposed to a broad spectrum of microbes duringnormal wear and become soiled relatively quickly. Routine cleaning anddisinfecting of the lenses are therefore required. Although thefrequency of cleaning and disinfecting may vary somewhat among differenttypes of lenses and lens care regimens, daily cleaning and disinfectingis normally required. Failure to clean and disinfect the lens properlycan lead to a multitude of problems ranging from mere discomfort whenthe lenses are being worn to serious ocular infections. Ocularinfections caused by particularly virulent microbes, such as Pseudomonasaeruginosa, can lead to loss of the infected eye(s) if left untreated orif allowed to reach an advanced stage before treatment is initiated. Itis therefore extremely important that patients disinfect their contactlenses in accordance with the regimen prescribed by their optometrist orophthalmologist.

[0004] Unfortunately, patients frequently fail to follow the prescribedregimens. Many patients find regimens to be difficult to understandand/or complicated, and as a result do not comply with one or moreaspects of the regimen. Other patients may have a negative experiencewith the regimen, such as ocular discomfort attributable to thedisinfecting agent, and as a result do not routinely disinfect theirlenses or otherwise stray from the prescribed regimen. In either case,the risk of ocular infections is exacerbated.

[0005] Despite the availability of various types of contact lensdisinfecting systems, such as heat, hydrogen peroxide, and otherchemical agents, there continues to be a need for improved systemswhich: 1) are simple to use, 2) have potent antimicrobial activity, and3) are nontoxic (i.e., do not cause ocular irritation as the result ofbinding to the lens material). There is also a need for chemicaldisinfecting agents that retain their antimicrobial activity in thepresence of salts (e.g., sodium chloride) and other components ofcompositions utilized to treat contact lenses. For example, U.S. Pat.No. 4,438,011 (Howes) states that ionic species such as chloride inhibitthe antimicrobial activity of the biguanide chlorhexidine, and teachesthat the concentration of such ionic species must therefore be limitedin order to maintain adequate antimicrobial activity for disinfectingcontact lenses.

[0006] There is also a need for an improved means of preservingpharmaceutical compositions from microbial contamination. This need isparticularly prevalent in the fields of ophthalmic and oticcompositions. The antimicrobial agents utilized to preserve aqueousophthalmic and otic compositions must be effective in preventingmicrobial contamination of the compositions when used at concentrationsthat are non-toxic to ophthalmic and otic tissues.

[0007] The present invention is directed to satisfying the above-citedneeds.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to certain aminobiguanideshaving antimicrobial activity and to pharmaceutical compositionscontaining one or more of these aminobiguanides to preserve thecompositions from contamination by microorganisms. The invention is alsodirected to the use of the subject aminobiguanides to disinfect contactlenses.

[0009] The aminobiguanides of the present invention have excellentantimicrobial activity, even at very low concentrations. These compoundsretain excellent antimicrobial activity, even in the presence ofsalt-containing media, such as saline solutions. The retention ofantimicrobial activity in the presence of sodium chloride and othersalts is highly significant, since such salts are commonly found inpharmaceutical compositions. For example, sodium chloride and othersalts are frequently used to adjust the osmolality of ophthalmiccompositions, so as to make the compositions isotonic with human tears.Sodium chloride or other salts may also be present in aqueous oticcompositions. Moreover, compositions utilized to treat contact lensesfrequently contain cleaning agents or other ingredients that may alsohave a negative effect on the activity of antimicrobial agents. Theability of the aminobiguanides of the present invention to retain a highlevel of antimicrobial activity, even in the presence of salts and otheringredients of pharmaceutical compositions, is therefore an importantfeature of the present invention.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0010] The aminobiguanide compounds of the present invention have thefollowing formula:

[0011] wherein:

[0012] R¹, R², R³ and R⁴ are the same or different and are selected fromhydrogen, alkyl (C₁ to C₂₀), aminoalkyl (C₁ to C₂₀), aryl, arylalkyl (C₃to C₂₀), aryloxyalkyl (C₃ to C₂₀) and cycloalkyl (C₃ to C₂₀); and X isalkyl (C₂ to C₂₀), optionally containing one or more substituentsselected from the group consisting of cycloalkyl (C₃ to C₂₀), aryl,arylalkyl (C₃ to C₂₀) and aryloxyalkyl (C₃ to C₂₀).

[0013] In the foregoing definitions of the R¹, R², R³, R⁴ and Xsubstituents, the alkyl groups may be saturated or unsaturated and maybe in the form of either straight or branched chains, and all of thegroups other than hydrogen may contain one or more heteroatoms. Thecompounds of the present invention also include pharmaceuticallyacceptable salts of the compounds of formula (I).

[0014] The preferred compounds of formula (I) are those wherein R¹, R²,R³ and R⁴ are selected from the group consisting of hydrogen, alkyl (C₁to C₂₀), aminoalkyl (C₁ to C₂₀) and cycloalkyl (C₃ to C₂₀), and X isselected from the group consisting of alkyl (C₂ to C₂₀) and alkyl (C₂ toC₂₀) substituted with one or more cycloalkyl (C₃ to C₂₀) groups.

[0015] The most preferred compounds are those wherein R¹, R², R³ and R⁴are hydrogen or C₁ to C₂₀ alkyl, and X is C₂ to C₁₀ alkyl or C₂ to C₁₀alkyl containing one or more cycloalkyl (C₃ to C₂₀) substituents.Examples of such compounds are set forth in the following table:Compound Number R¹ R² R³ R⁴ X 1 CH₃ CH₃(CH₂)₁₁ H 1,4-dimethylpentyl(CH₂)₃ 2 CH₃ CH₃(CH₂)₁₁ H heptyl (CH₂)₃ 3 CH₃ CH₃(CH₂)₁₁ H benzyl (CH₂)₃4 CH₃ CH₃(CH₂)₁₁ H decyl (CH₂)₃ 5 CH₃ CH₃(CH₂)₁₁ H N-methyl-N- (CH₂)₃dodecyl amino propyl

[0016] The compound wherein X is propyl, R¹ is methyl, R² is dodecyl, R³is hydrogen and R⁴ is 1,4-dimethylpentyl (i.e., Compound Number 1) isthe most preferred compound for formula (I).

[0017] The compounds of formula (I) may be synthesized in accordancewith the following reaction scheme:

[0018] Suitable methods for synthesizing the compounds of formula (I)are further demonstrated by the following examples, which describe thesynthesis of certain preferred compounds:

EXAMPLE 1

[0019] Synthesis of Compound Number 1:

[0020] A mixture of 2,5-dimethylhexylamine hydrochloride (3 g. 19.9 mM)and 1.96 g (22 mM) of sodium dicyanamide in 30 ml of 1-butanol wasreacted under reflux for 6 hours and concentrated in vacuo. This wassuspended in 200 ml of water and extracted with chloroform (2×200 ml).The organic layer was washed with water and dried over MgSO₄ andconcentrated in vacuo. This residue was crystallized from ethylacetate-n-hexane to yield 3.0 g. (75% yield). Nmr(CDCl₃) δ 5.3 (m, 3H),3.6 (m, 1H)), 1.6 (s, 3H), 1.6-1.4 (m, 3H), 1.3 (m, 5H), and 0.9 (d, 6).This material was used without further purification. To a pressurebottle added 8.0 g (24.3 mM) of N, N-dodecylmethyl-1,3-propanediaminedihydrochloride, 6.23 g (34.4 mM) of 1,4-dimethylpentylcyanoguanidineand 1.5 mL of amyl alcohol. The bottle was sealed and heated to 150° C.Melting began at about 119° C. and the reaction mixture was stirred at150° C. for 4 hrs. after which ethanol was added to dissolve thematerial. This material was acidified with concentrated HCl to pH 0-1and precipitated with acetone to yield white material. This wascrystallized from isopropanol-acetone to give the desired compound as awhite crystal. Elemental Analysis: Calcd. for C₂₅H₅₇N₆C₁₃(549.14): C,54,68; H, 10.65; N, 15.31; Cl, 19.37 Found: C, 55.06; H, 10.44; N,15.14; Cl, 19.10. Nmr (DMSO-d6): δ 3.7 (m, 1H), 3.3 (m, 4H), 3.0 (m,2H), 2.8 (s, 3H, N—CH₃), 2.1 (b. 2H), 1.8 (b, 2H), 1.5 (b, 2H), 1.3 (m,21H), and 0.9 (d, 6H, CH₃). LC/MS also confirmed the above structure.

EXAMPLE 2

[0021] Synthesis of Compound Number 2:

[0022] By following the procedure described in the synthesis of Compound1 (see Example 1, above) with a mixture of 0.658 g (0.658 g., 2 mM) ofN,N-dodecylmethyl-1,3-propanediamine dihydrochlorides and 0.346 g (2 mM)of n-hexylcyanoguanidine, 0.5 g (49% yield) of the desired product wasobtained. Elemental Analysis: Calcd. for C₂₅H₅₈N₆C₁₃: C, 54.68; H,10.65; N, 15.31; Cl, 19,37 Found:, C, 54.71; H, 10.26; N, 15.29; Cl;19.19 Nmr (DMSO-d6): 6 3.4-2.9 (m, 8H), 2.7(s, 3H, N—CH3), 1.9 (b, 2H),1.7 (b, 2H), 1.5 (b, NHCH₂CH₂, 2H), 1.3. (app. s, 26H), and 0.9 (t, 3H,CH₃).

EXAMPLE 3

[0023] Synthesis of Compound Number 3:

[0024] 14.3 g (0.1 M) of benzylamine hydrochloride was reacted with 8.9g (0.1 M) of sodium dicyanamide in 100 ml of n-butanol at 150° C. for 5hrs. and treated with 50 ml of water. The collected organic layer waswashed with 0.1N HCl (2×50 ml) and water (1×50 ml) consequently andconcentrated in vacuo to leave a viscous material which was taken up byethyl acetate. This was dried over MgSO₄ and crystallized fromethylacetate-hexane to afford 13 g (75% yield). m.p. 95-100° C. Withoutfurther purification, this was used for the next reaction. By followingthe same procedure as described in the synthesis of Compound 1, with0.987 g (3 mM) of N,N-dodecylmethyl-1,3-propanediamine dihydrochloridesand 0.678 g (3.9 mmol) of the above cyanoguanidine, the desired compoundwas obtained. Elemental Analysis: Calcd. for C₂₅H₄₉N₆Cl₃: C, 55.60; H,9.14; N, 15.56; Cl 19.69 Found: C, 55.32; H, 9.25; N, 15.53; C, 19.36.Nmr. (DMSO-d₆) δ 7.35 (app. s, C₆H₅, 5H), 4.4 (s, 2H, CH₂C₆H₅), 3.2 (t,2H), 3.0 (broad, 4H), 2.7 (s, 3H, N—CH₃), 1.9 (m, 2H), 1.6 (t, 3H), 1.3(app. s, 18H), and 0.9 (t, 3H, CH₃-CH₂).

EXAMPLE 4

[0025] Synthesis of Compound Number 4:

[0026] The same procedure as described in the synthesis of Compound 1(see Example 1, above) was utilized with 0.73 g (2.2 mM) ofN,N-dodecylmethyl-1,3-propanediamine dihydrochlorides and 0.5 g (2.2 mM)of decylcyanoguanidine to afford 0.5 g (38.6%) of the desired product.Elemental analysis: Calcd. for C₂₈H₆₃N₆Cl₃ (590.20): C, 56.98; H, 10.76;N, 14.24; Cl, 18.02 Found: C, 56.68; H, 10.62; N, 14.19; Cl, 17.85 Nmr.(CDCl₃) δ 2.9 (N—CH₃), 2.3 (broad, 2H), 1.9 (broad, 2H), 1.7 (broad, 2H)1.5 (s, 32H), and 1.1 (t, 6H).

EXAMPLE 5

[0027] Synthesis of Compound Number 5:

[0028] A mixture of N,N-dodecylmethyl-1,3-propanediamine dihydrochloride(2.0 g. 6.1 mM) and 0.7 g (7.9 mM) of sodiumdicyanamide was reacted in40 ml n-butanol under reflux for 5 hrs and aqueous NaHCO₃ was added. Theorganic layer was separated and dissolved in chloroform solution. Thischloroform solution was washed with aqueous NaHCO₃ and watersuccessively and concentrated in vacuo. This residue was crystallizedfrom methanol. m.p. 80-81. Elemental Analysis: Calcd. for C₁₈H₃₇N₅(323.53) C, 66.83; H, 11.53; N, 21.65 Found: C, 66.39; H, 11.51; N,21.71. Nmr (CD₃OD) δ 3.2 (t, 2H), 2.4 (m, 4H), 2.2 (s, 3, N-CH3), 1.7(m, 2H), 1.5 (m, 2H), 1.3 (s, 18H), and 0.9 (t, 3H). This cyanoguanidine(0.5 g, 1.5 mM) was reacted with 0.51 g (1.5 mM) of dihydrochloride saltof N,N-dodecylmethyl-1,3-propanediamine in 0.5 ml of amylalcohol at 155°C. for 3 hrs and precipitated with acetone. The precipitate wasdissolved in ethanol and adjusted to pH 1.0 with HCl. This wasconcentrated in vacuo and crystallized from ethanol to afford 0.71 g.(70% yield). Elemental analysis: Calcd. for C₃₄H₇₃N₇.4HCl (726.26): C,56.23; H, 10.69; N, 13.56; Cl 19.53 Found: C, 55.86; H, 10.30; N, 13.71;Cl, 19.20. LC/MS confirmed the above structure. Nmr (DMSO-d₆) δ 3.3-2.9(m, 12H), 2.7 (s, 6H, NCH₃), 1.9 (b, 4H), 1.6 (b, 4H), 1.3 (s, 36H), and0.8 (t, 6H, CH₃).

[0029] The compounds of formula (I) can be used individually, incombination with one or more other compounds of formula (I), or incombination with other disinfectants or preservatives. The compoundsmay, for example, be used in combination with the polymeric quaternaryammonium compounds described in U.S. Pat. No. 4,407,791; the entirecontents of that patent are hereby incorporated in the presentspecification by reference. As described in the '791 patent, thosepolymeric quaternary ammonium compounds are useful in disinfectingcontact lenses and preserving ophthalmic compositions. The mostpreferred polymeric quaternary ammonium compound is polyquatemium-1.Such polymeric quaternary ammonium compounds are typically utilized inan amount of from about 0.0001 to 0.01 percent weight/volume (“w/v %”).For the agent polyquaternium-1, a concentration of 0.001 w/v % ispreferred.

[0030] The amount of each compound used will depend on the purpose ofthe use, e.g., disinfection of contact lenses or preservation ofpharmaceutical compositions, and the absence or inclusion of otherantimicrobial agents. The concentrations determined to be necessary forthe above-stated purposes can be functionally described as “an amounteffective to disinfect” and “an amount effective to preserve” orvariations thereof. The concentrations used for disinfection willgenerally be in the range of from about 0.0001 to about 0.1 percent w/v% (“w/v %”). The concentrations used for preservation will generally bein the range of from about 0.00001 to about 0.01 w/v %.

[0031] The compositions of the present invention may be aqueous ornonaqueous, but will generally be aqueous. As will be appreciated bythose skilled in the art, the compositions may contain a wide variety ofingredients, such as tonicity agents (e.g., sodium chloride ormannitol), surfactants (e.g., polyvinyl pyrrolidone andpolyoxyethylene/polyoxypropylene copolymers), viscosity adjusting agents(e.g., hydroxypropyl methyl cellulose and other cellulose derivatives)and buffering agents (e.g., borates, citrates, phosphates andcarbonates). As indicated above, the ability of the compounds of formula(I) to retain their antimicrobial activity in the presence of suchagents is a significant advantage of the present invention.

[0032] The ophthalmic compositions of the present invention will beformulated so as to be compatible with the eye and/or contact lenses tobe treated with the compositions. As will be appreciated by thoseskilled in the art, the ophthalmic compositions intended for directapplication to the eye will be formulated so as to have a pH andtonicity that are compatible with the eye. This will normally require abuffer to maintain the pH of the composition at or near physiologic pH(i.e., 7.4) and may require a tonicity-adjusting agent (e.g., NaCl) tobring the osmolality of the composition to a level that ranges fromslightly hypotonic to isotonic, relative to human tears. This rangecorresponds to an osmolality of from about 220 to about 320 milliosmolesper kilogram water (“mOsm/kg”).

[0033] The formulation of compositions for treating contact lenses(e.g., disinfecting and/or cleaning) will involve similarconsiderations, as well as considerations relating to the physicaleffect of the compositions on contact lens materials and the potentialfor binding or absorption of the components of the composition by thelens. The contact lens disinfecting compositions of the presentinvention will preferably be formulated as aqueous solutions, but mayalso be formulated as nonaqueous solutions, as well as suspensions,gels, and so on. The compositions may contain a variety of tonicityagents, surfactants, viscosity adjusting agents and buffering agents, asdescribed above.

[0034] The above-described compositions may be used to disinfect contactlenses in accordance with processes known to those skilled in the art.More specifically, the lenses will first be removed from the eyes of thepatients, and then will be immersed in the compositions for a timesufficient to disinfect the lenses. This immersion will typically beaccomplished by means of soaking the lenses in a solution overnight(i.e., approximately six to eight hours). The lenses will then be rinsedand placed in the eye. Prior to immersion in the disinfectingcompositions, the lenses will preferably also be cleaned and rinsed.

[0035] The compositions and methods of the present invention may be usedin conjunction with various types of contact lenses, including bothlenses generally classified as “hard” and lenses generally classified as“soft”.

[0036] The compounds of formula (I) may also be included in varioustypes of pharmaceutical compositions as preservatives, so as to preventmicrobial contamination of the compositions. The types of compositionswhich may be preserved by the compounds of formula (I) include:ophthalmic pharmaceutical compositions, such as topical compositionsused in the treatment of glaucoma, infections, allergies orinflammation; otic pharmaceutical compositions, such as topicalcompositions used in the treatment of bacterial infections orinflammation of the ear; compositions for treating contact lenses, suchas cleaning products and products for enhancing the ocular comfort ofpatients wearing contact lenses; other types of ophthalmic compositions,such as ocular lubricating products, artificial tears, astringents, andso on; dermatological compositions, such as antiinflammatorycompositions, as well as shampoos and other cosmetic compositions; andvarious other types of pharmaceutical compositions.

[0037] The present invention is not limited with respect to the types ofpharmaceutical compositions in which the compounds of formula (I) may becontained as preservatives, but the compounds are particularly useful inpreserving ophthalmic and otic compositions from microbialcontamination. The compounds are particularly useful in these types ofcompositions due to the ability of the compounds to exhibit apreservative effect at very low concentrations, without adverselyaffecting ophthalmic and otic tissues.

[0038] The following examples are provided to further illustrate the useof the compounds of formula (I) in pharmaceutical compositions and todemonstrate the antimicrobial activity of the compounds.

EXAMPLE 6

[0039] The following formulation represents an example of a contact lensdisinfecting solution of the present invention. In this formulation, theaminobiguanide compounds of the present invention function to preservethe formulation from microbial contamination during storage. Thecompounds also function as an active disinfecting agent when theformulation is applied to contact lenses. Ingredient Concentration (w/v%) Compound 0.0005 Sorbitol 1.2 AMP-95 ™ 0.45 Sodium Citrate 0.65 SodiumChloride 0.1 Boric Acid 0.6 EDTA 0.05 Tetronic 1304 ™ 0.05 PurifiedWater q.s. 100 HCl/NaOH q.s. pH 7.8

[0040] In the foregoing formulation, the term “Compound” is intended torepresent any of the aminobiguanides of formula (I). The formulation isan aqueous, isotonic solution. The solution can be prepared bysequentially dissolving each ingredient in water, and adjusting the pHof the resulting solution, if necessary.

EXAMPLE 7

[0041] The following formulation represents another example of a contactlens disinfecting solution of the present invention: IngredientConcentration (w/v %) Compound 0.001 Boric Acid 0.58 Sodium Borate 0.18Disodium EDTA 0.05 Sodium Chloride 0.49 Purified Water q.s. 100 NaOH/HCIq.s. pH 7.0

[0042] The foregoing formulation is an aqueous, isotonic solution. Itcan be prepared in the same manner as the solution of Example 6 above.

EXAMPLE 8

[0043] The antimicrobial activity of the solution of Example 6,containing 0.0005 w/v % of the aminobiguanide identified above asCompound No. 1, was evaluated relative to three key microorganisms. Theevaluation was conducted by determining the extent to which the solutionreduced an initial population of about 10⁶/mL microorganisms over time.The results were as follows: Log₁₀ Reduction Log₁₀ ReductionMicroorganism at 6 hours at 24 hours Candida albicans 2.1 5.0 Serratiamarcescens 3.9 6.1 Staphlococcus aureus 3.7 4.9

[0044] These results demonstrate that the aminobiguanides of formula (I)have potent antimicrobial activity.

EXAMPLE 9

[0045] The antimicrobial activity of the solution of Example 7,containing 0.0005 w/v % of Compound No. 1, was also evaluated usingessentially the same procedure as those described in Example 8 above.The results were as follows: Log₁₀ Reduction Log₁₀ ReductionMicroorganism at 6 hours at 24 hours Candida albicans 1.4 4.0 Serratiamarcescens 3.0 4.8 Staphlococcus aureus 3.4 4.6

[0046] These results further demonstrate the potent antimicrobialactivity of the aminobiguanides of the present invention.

EXAMPLE 10

[0047] The antimicrobial activity of Compound No. 1 at a concentrationof 0.0005 w/v % in water was also evaluated. The results were asfollows: Log₁₀ Reduction Log₁₀ Reduction Microorganism at 6 hours at 24hours Candida albicans 2.1 3.8 Serratia marcescens 5.5 3.9Staphylococcus aureus 4.1 6.0

[0048] These results demonstrate that the antimicrobial activity of thesolutions tested in Examples 8 and 9 above is attributable to theaminobiguanide of the present invention (i.e., Compound No. 1), ratherthan other components of the solutions.

[0049] A comparison of the activity of Compound No. 1 when contained ina distilled water vehicle to the activity of Compound No. 1 whencontained in buffered, isotonic solutions shows that the aminobiguanidesof the present invention retain their antimicrobial activity whenutilized in the presence of sodium chloride and other excipientscommonly contained in pharmaceutical compositions. This retention ofactivity is apparent from a comparison of the antimicrobial activitydemonstrated in Examples 8 and 9 with the antimicrobial activitydemonstrated in Example 10.

What is claimed is:
 1. A sterile pharmaceutical composition fordisinfecting contact lenses, comprising a compound of the followingformula, in an amount effective to disinfect the lens:

wherein: R¹, R^(2,) R³ and R⁴ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl (C₁ to C₂₀), aminoalkyl (C₁to C₂₀), aryl, arylalkyl (C₃ to C₂₀), aryloxyalkyl (C₃ to C₂₀) andcycloalkyl (C₃ to C₂₀); and X is alkyl (C₂ to C₂₀), optionallycontaining one or more substituents selected from the group consistingof cycloalkyl (C₃ to C₂₀), aryl, arylalkyl (C₃ to C₂₀) and aryloxyalkyl(C₃ to C₂₀), or a pharmaceutically acceptable salt thereof, and anaqueous vehicle therefor.
 2. A composition according to claim 1, whereinR¹, R², R³ and R⁴ are selected from the group consisting of hydrogen,alkyl (C₁ to C₂₀), benzyl and 1,4-dimethylpentyl, and X is selected fromthe group consisting of alkyl (C₂ to C₁₀) and alkyl (C₂ to C₁₀)substituted with cycloalkyl (C₃ to C₂₀).
 3. A composition according toclaim 2, wherein X is propyl, R¹ is methyl, R² is dodecyl, R³ ishydrogen, and R⁴ is selected from the group consisting of1,4-dimethylpentyl, heptyl, benzyl, decyl and N-methyl-N-dodecyl aminopropyl.
 4. A composition according to claim 2, wherein R¹ is methyl, R²is dodecyl, R³ is hydrogen, R⁴ is 1,4-dimethylpentyl and X is propyl. 5.A composition according to claim 1, wherein the composition furthercomprises 0.001 to 0.01 w/v % of a polymeric quaternary ammoniumcompound.
 6. A composition according to claim 5 wherein the polymericquaternary ammonium compound comprises polyquatemium-1 at aconcentration of 0.001 w/v %.
 7. A method of disinfecting a contact lenswhich comprises applying the composition of claim 1 to the lens for atime sufficient to disinfect the lens.
 8. A method according to claim 7,wherein the lens is soaked in the composition for at least four hours.9. A compound of the following formula:

wherein: R¹, R^(2,) R³ and R⁴ are selected from the group consisting ofhydrogen, alkyl (C₁ to C₂₀), aminoalkyl (C₁ to C₂₀) and cycloalkyl (C₃to C₂₀); and X is selected from the group consisting of alkyl (C₂ toC₁₀) and alkyl (C₂ to C₁₀) substituted with cycloalkyl (C₃ to C₂₀); or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 9, wherein R¹, R², R³ and R⁴ are selected from the groupconsisting of hydrogen and alkyl (C₁ to C₂₀).
 11. A compound accordingto claim 10, wherein X is propyl, R¹ is methyl, R² is dodecyl, R³ ishydrogen, and R⁴ is selected from the group consisting of1,4-dimethylpentyl, heptyl, decyl and N-methyl-N-dodecyl amino propyl.12. A compound according to claim 11, wherein R¹ is methyl, R² isdodecyl, R³ is hydrogen, R⁴ is 1,4-dimethylpentyl, and X is propyl. 13.A pharmaceutical composition comprising an amount of a compound of claim9 effective to preserve the composition from microbial contamination.14. A pharmaceutical composition according to claim 13, wherein thecomposition is an aqueous ophthalmic composition.
 15. A pharmaceuticalcomposition according to claim 13, wherein the composition is an aqueousotic composition.
 16. A pharmaceutical composition according to claim13, wherein the composition is utilized to treat contact lenses.
 17. Apharmaceutical composition according to claim 16, wherein thecomposition contains a compound of formula (I) wherein R¹, R², R³ and R⁴are selected from the group consisting of hydrogen and alkyl (C₁ toC₂₀), and X is selected from the group consisting of alkyl (C₂ to C₁₀)and alkyl (C₂ to C₁₀) substituted with cycloalkyl (C₃ to C₂₀).
 18. Apharmaceutical composition according to claim 17, wherein thecomposition contains a compound of formula (I) wherein X is propyl, R¹is methyl, R² is dodecyl, R³ is hydrogen, and R⁴ is selected from thegroup consisting of 1,4-dimethylpentyl, heptyl, benzyl, decyl andN-methyl-N-dodecyl amino propyl.
 19. A pharmaceutical compositionaccording to claim 18, wherein the composition contains a compound offormula (I) where R¹ is methyl, R² is dodecyl, R³ is hydrogen, R⁴ is1,4-dimethylpentyl and X is propyl.